PROJECT SUMMARY Cardiovascular disease (CVD) is a heterogeneous disease encompassing a broad range of heart and vasculature disorders and is the number one cause of death worldwide. A well-established relationship exists between quantitative variation in the plasma lipid levels and CVD risk; however, the exact mechanism is unclear. Lipids play a crucial role in cell, tissue and organ physiology, and their metabolism is tightly regulated; however, in many human diseases lipid metabolism is disrupted. The classical lipid parameters (HDL-C, LDL-C, and triglycerides) most commonly examined in relation to disease risk are themselves complex entities composed of multiple lipid species. We hypothesize that these basic lipid species represent unique phenotypes that are better predictors of disease risk and may lead to the more rapid discovery of genes causally involved in lipid variation and cardiovascular disease. In this project we will exploit whole genome sequence (WGS) information using a mixed longitudinal design in powerful extended pedigrees of Mexican American individuals in combination with comprehensive measures of the human lipidome, to identify novel genes and functional variants influencing lipid variation and risk of CVD development. This project will generate novel lipid endophenotypes that may represent better predictors of disease risk. The combination of these precise biological phenotypes and WGS gives us an unprecedented opportunity to identify novel genes and functional variants influencing human lipid variation and risk of CVD. To achieve these objectives, we will (I) perform untargeted lipid profiling in 500 Mexican American individuals from seven large SAFS pedigrees, identify those species genetically correlated with CVD-related traits and incorporate these into a targeted assay to profile in all individuals; (II) perform targeted lipid profiling in 2,500 Mexican American individuals followed by quantitative genetic analyses; (III) identify novel sequence variation influencing lipid variation and CVD risk in all individuals using WGS; (IV) perform replication in an independent Mexican American population, the Cameron County Hispanic Cohort. CVD is the leading cause of death globally, posing a huge economic burden. The ability to identify genes that are causally involved in disease risk provides an unparalleled opportunity to quickly determine biological pathways that are involved in disease pathology. A better understanding of the genetic contribution to lipid variation and CVD development will provide novel approaches for the characterization, treatment and potential prevention of this costly disease.